Evidence on the efficacy and safety of low-dose direct oral anticoagulant (DOAC) in older patients with nonvalvular atrial fibrillation is still scarce. We conducted a single-center prospective registry of patients with nonvalvular atrial fibrillation treated with DOACs: the DIRECT registry (n = 2,216; follow-up, 407 ± 388 days, UMIN000033283). The whole population was divided into 2 groups: the older group (age ≥80 years, n = 548) versus the younger group (age <80 years, n = 1,668). Primary safety and efficacy end points were major bleeding according to the International Society on Thrombosis and Haemostasis criteria, and stroke or systemic embolism (SSE), respectively. Effects of known risk factors and low-dose DOAC on major bleeding and SSE were assessed using a multivariable Cox proportional hazards model. In the older group, low-dose DOAC was associated with lower bleeding events (hazard ratio 0.279, 95% confidence interval 0.087 to 0.892, p = 0.031) but was not associated with increased SSE (p = 0.894). In the younger group, low-dose DOAC was neither associated with risk of major bleeding nor SSE (both p >0.05). In conclusion, in older patients, low-dose DOAC was associated with reduced risk of major bleeding without compromising its efficacy.
Direct oral anticoagulant (DOAC) is an established standard therapy for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). The dose adjustment standards are uniformly applied to young patients and old patients. However, it remains to be investigated if we can apply the standard to especially older patients because age-related physiological and pharmacokinetic changes will complicate drug therapy in older patients. We aimed to test the hypothesis that bleeding and thromboembolic risk factors in older patients might be different from those of younger patients, and old patients require the differential dose adjustment approach.
We conducted a single-center prospective observational registry of patients with NVAF with DOAC, safety and effectiveness of 4 different DOACs, dabigatran, rivaroxaban, apixaban and edoxaban in the real-world clinical practice (DIRECT) registry (UMIN000033283). All serial adult patients (aged ≥18 years) with NVAF at Osaka Police Hospital, who were users of dabigatran, rivaroxaban, apixaban, or edoxaban from June 2011 to November 2017, were enrolled. If a patient ever used DOAC during the study period, the first fill of DOAC was defined as the index medication. The treatment period was defined as the time from the first use of a drug to last follow-up or 2 days after the trial drugs were discontinued if the patient stopped the medication. The analysis was performed under the intention-to-treat framework on the full analysis set of patients. The study was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all enrolled patients. This study was approved by the Osaka Police Hospital Ethics Committee. We used the data set of the DIRECT registry to evaluate the difference in bleeding and thromboembolic risk factors between younger and older patients. The whole population was divided into 2 groups: the older group (aged ≥80 years) versus the younger group (aged <80 years).
In the current sub-analysis of the DIRECT registry, we categorized DOAC dosing into 5 groups: appropriate standard-dose, appropriate low-dose, over-dose, under-dose, and contraindication. Low-dose was defined as a composite of appropriate low-dose and under-dose. Patients with under-dose of DOAC indicate those who should have a standard dose of DOAC but had a reduced dose at a physician’s discretion. Patients with over-dose of DOAC indicate those who should have a reduced dose of DOAC but had a standard dose at a physician’s discretion. Standard criteria of dose reduction for each DOAC were summarized in the online supplement.
Primary safety and efficacy end points were major bleeding according to the International Society on Thrombosis and Haemostasis criteria, and stroke or systemic embolism (SSE), respectively. Major bleeding was defined according to the following International Society on Thrombosis and Haemostasis criteria: (1) fatal bleeding; and/or (2) symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome); and/or (3) bleeding causing a fall in hemoglobin level of ≥20 g/L (1.24 mmol/L), or leading to transfusion of ≥2 units of whole blood or red cells. Stroke was defined as a neurologic deficit persisting ≥24 hours attributed to an acute focal injury of the central nervous system by a vascular cause, including cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage. Systemic embolism was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (e.g., atherosclerosis, instrumentation). Clinical events were monitored by questioning, physical examination, laboratory test, and electrocardiogram at each outpatient visit every 2 to 4 months. An independent clinical event committee whose members were unaware of the treatment group adjudicated all clinical events.
All analyses were performed using IBM SPSS, version 26.0. (IBM Corporation, Armonk, New York) or R software (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria). p value of <0.05 was considered statistically significant. Categorical variables are expressed as n (%) and were compared using the chi-square test or Fisher’s exact test. Continuous variables are expressed as mean ± SD or median (interquartile range) and were compared using the Student t test, Mann-Whitney U test, ANOVA, or Kruskal-Wallis test, as appropriate. Survival was displayed using the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HRs) with 95% confidence interval (CI) were estimated using the Cox proportional hazards model. Effects of known risk factors and low-dose DOAC on major bleeding and SSE were assessed using the multivariable Cox proportional hazards model including the following factors: low-dose DOAC, age, female gender, body weight ≤45 kg, hypertension, diabetes mellitus, vascular disease, previous bleeding, previous stroke, previous heart failure, renal function, liver dysfunction, anemia, and antiplatelet therapy. These factors were determined by reference to the components of the HAS-BLED score, ORBIT score, CHADS 2 score and bleeding risk factors in the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial. Because existing bleeding and thrombotic risk factors have been found in the younger population, it is not clear if they are fully applicable to older patients. Therefore, we included these covariates all together in the models for both major bleeding and SSE.
A total of 2,216 patients (dabigatran, n = 648; rivaroxaban, n = 538; apixaban, n = 599; and edoxaban, n = 431) were enrolled in the present registry. The older group and the younger group consisted of 548 and 1,668 patients, respectively. Baseline characteristics of each group are listed in Table 1 . The prevalence of bleeding and stroke risk factors in both groups is shown in Figure 1 .
| Variable | Age ≥ 80 years(N = 548) | Age < 80 years(N = 1,668) | p Value |
|---|---|---|---|
| Age (years) | 84.16 ±3.45, 84.00 [81.00, 87.00] | 67.46 ±9.09, 70.00 [63.00, 74.00] | <0.001 |
| Body weight (kg) | 52.89 ±11.85, 52.15 [26.80, 164.00] | 63.47 ±13.94, 63.10 [32.00, 126.20] | <0.001 |
| BMI (kg/m 2 ) | 22.03 ±4.07, 21.90 [19.35, 24.20] | 23.78 ±3.95, 23.60 [21.20, 26.00] | <0.001 |
| Woman | 287 (52.4%) | 519 (31.1%) | <0.001 |
| Hypertension | 449 (81.9%) | 1,179 (70.7%) | <0.001 |
| Diabetes mellitus | 139 (25.4%) | 480 (28.8%) | 0.136 |
| Dyslipidemia | 325 (59.3%) | 1,119 (67.1%) | 0.001 |
| Statin use | 183 (33.4%) | 582 (34.9%) | 0.551 |
| Number of antiplatelets | 0.001 | ||
| None | 400 (73.0%) | 1,339 (80.3%) | |
| Single | 129 (23.5%) | 282 (16.9%) | |
| Dual | 19 (3.5%) | 47 (2.8%) | |
| Type of antiplatelets | |||
| Aspirin | 109 (19.9%) | 250 (15.0%) | 0.008 |
| Cilostazol | 18 (3.3%) | 25 (1.5%) | 0.014 |
| Clopidogrel | 35 (6.4%) | 93 (5.6%) | 0.548 |
| Ticlopidine | 3 (0.5%) | 4 (0.2%) | 0.5 |
| Prasugrel | 2 (0.4%) | 4 (0.2%) | 0.988 |
| Persistent or longstanding AF | 240 (44.0%) | 641 (38.5%) | 0.026 |
| Prior heart failure | 212 (38.7%) | 313 (18.8%) | <0.001 |
| Prior bleeding | 204 (37.2%) | 397 (23.8%) | <0.001 |
| Prior stroke | 177 (32.3%) | 270 (16.2%) | <0.001 |
| Vascular disease | 180 (32.8%) | 386 (23.1%) | <0.001 |
| Coronary artery disease | 134 (24.5%) | 305 (18.3%) | 0.002 |
| Peripheral vascular disease | 68 (13.4%) | 90 (6.6%) | <0.001 |
| Prior PCI or CABG | 80 (14.7%) | 159 (9.5%) | 0.001 |
| Liver dysfunction | 155 (28.3%) | 582 (34.9%) | 0.005 |
| Creatinine (mg/dL) | 0.95 ±0.34, 0.90 [0.72, 1.10] | 0.86 ±0.27, 0.82 [0.68, 0.98] | <0.001 |
| Creatinine clearance (ml/min) | 43.77 ±15.89, 42.92 [32.14, 53.82] | 76.88 ±29.00, 72.28 [57.29, 91.16] | <0.001 |
| Hemoglobin (g/dL) | 12.50 ±1.83, 12.50 [11.20, 13.70] | 13.58 ±1.95, 13.60 [12.40, 15.00] | <0.001 |
| Anemia | 272 (49.6%) | 494 (29.6%) | <0.001 |
| Modified HAS-BLED score * † | 3.08 ±1.15, 3.00 [2.00, 4.00] | 2.37 ±1.28, 2.00 [2.00, 3.00] | <0.001 |
| ORBIT score * | 3.59 ±1.69, 4.00 [2.00, 5.00] | 1.84 ±1.72, 2.00 [0.00, 3.00] | <0.001 |
| CHADS 2 score | 3.11 ±1.27, 3.00 [2.00, 4.00] | 1.73 ±1.27, 2.00 [1.00, 3.00] | <0.001 |
| CHA2DS2-VASc score | 4.88 ±1.55, 5.00 [4.00, 6.00] | 2.88 ±1.72, 3.00 [2.00, 4.00] | <0.001 |
| Type of DOAC | <0.001 | ||
| Dabigatran | 82 (15.0%) | 566 (33.9%) | |
| Rivaroxaban | 103 (18.8%) | 435 (26.1%) | |
| Apixaban | 201 (36.7%) | 398 (23.9%) | |
| Edoxaban | 162 (29.6%) | 269 (16.1%) | |
| Low-dose DOAC | 481 (87.8%) | 707 (42.4%) | <0.001 |
| Under dose | 58 (10.6%) | 280 (16.8%) | |
| Appropriate low dose | 413 (75.4%) | 420 (25.2%) | |
| Contraindication | 10 (1.8%) | 7 (0.4%) |
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